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Unformatted text preview: the trial reports as a safe and effective means of treating vascular dementia. After a pooled analysis of the two trials, the authors wrote that “the results ... are somewhat confusing,” and “further data on donepezil’s impact on executive functioning would be certainly desirable” [18,19]. At the time of writing this article, the data from these vascular dementia trials have not been considered sufﬁcient evidence to license donepezil for treating vascular dementia. However, the positive messages contained in the published RCTs may promote the offlabel use of the drug. Dementia Associated with Parkinson Disease and Dementia with Lewy Bodies
A Cochrane systematic review identiﬁed only one RCT (involving 120 patients) of the efﬁcacy of rivastigmine in patients with probable dementia with Lewy bodies [20,21]. The Cochrane reviewers concluded that the trial “showed no statistically signiﬁcant difference between the two groups at 20 weeks. A possible beneﬁcial effect on neuropsychiatric features was found only in analysis of observed cases, and may therefore be due to bias.” Hence the evidence of any beneﬁt is currently weak . Two clinical trials have investigated the effect of cholinesterase inhibitors in patients with dementia associated with Parkinson disease. The ﬁrst one , which found a trend (not statistically signiﬁcant) toward better scores on the ADAS-cog is not further discussed here because of its small size (only 22 patients were randomized to receive donepezil or placebo). The second trial, by Emre et al., investigated the effect of rivastigmine in 541 highly selected patients recruited from an unspeciﬁed number of centers from 12 countries . Patients included in the trial had received a diagnosis of dementia 6.6 ± 5.2 years (treated arm) and 7.3 ± 5.2 years (placebo arm) after the diagnosis of Parkinson disease. It would be difﬁcult to ﬁnd such a population in a clinical setting for a number of reasons. Beyond the diagnostic challenge of differentiating dementia associated with Parkinson disease from dementia of the Lewy body type, there is also evidence that the risk of dementia in Parkinson disease is associated with age and severity of extrapyramidal signs, and the mean time from onset of Parkinson disease to dementia is estimated to be 10.5 years [24–26]. But the exact clinical implications of this RCT are still not clear. The outcome measures used in Emre and colleagues’ trial were the ADAS-cog and the Alzheimer Disease Cooperative Study–Clinician’s Global Impression of Change scale. In their trial, the authors considered a mean improvement of 2.25 points in the ADAS-cog score as clinically meaningful, even though this scale has never been used to monitor the progression rate of dementia in Parkinson disease. Among adverse events, Parkinsonian symptoms were reported more frequently in Clinicians should be careful about generalizing RCT results to their own patients.
the rivastigmine group than in the placebo group. The authors concluded that rivastigmine was associated with moderate but signiﬁcant improvements in all symptoms of dementia associated with Parkinson disease, but also with high rates of adverse events, and that the ﬁndings may have implications for clinical practice. But the exact clinical implications of this RCT are still not clear. Mild Cognitive Impairment: A New Clinical Entity or a New Market Frontier?
Whether MCI can be considered a clinical entity is still a matter of debate (for example, Gauthier and Touchon have argued that “there is epidemiological evidence that many subjects labeled as having MCI do not worsen over time and may revert to normal cognitive abilities” ). Nevertheless, speciﬁc drug treatment for MCI has been proposed. Two RCTs have been conducted to investigate whether donepezil delays the onset of dementia in people with MCI. These studies failed to demonstrate any efﬁcacy, while showing a worse safety proﬁle among patients receiving active drug compared with the placebo group. In the ﬁrst published trial , signiﬁcant treatment effects were not seen in the primary efﬁcacy measures, while more patients treated with donepezil experienced adverse events compared with patients treated with placebo (88% versus 73%). Despite this negative result, a new trial was conducted by Petersen et al., comparing donepezil, vitamin E, and placebo . This study did not show a signiﬁcant difference among the three groups in the rate of progression from MCI to Alzheimer disease over a three-year period. Nevertheless, the authors stress some limited effects on secondary measures: a reduced likelihood of progression to Alzheimer disease only during the ﬁrst 12 months of treatment, and a beneﬁt of donepezil among carriers of one or more apolipoprotein E ε4 throughout the three-year follow-up. This latter claim, in particular, was not supported by the data as the study was not statistically powered to evaluate the effect of the treatment in separate groups of apolipoprotein E ε4 carriers. Harms-related data were inadequate: the ﬂow of participants through the study phases was not described; the reasons and timing for discontinuation per treatment arm were not reported; only adverse events observed in at least 5% of patients were reported; and the causes of the 23 deaths observed (17 in the double-blind phase and six in the subsequent open-label phase) were not speciﬁed. In the double-blind phase, a higher number of deaths was observed in the donepezil arm (n = 7) compared with the vitamin E arm (n = 5) and the placebo arm (n = 5). For the six deaths that occurred during the open-label phase, the original arm (active drug or placebo in the previous double-blind phase) was not reported. (The distribution of these six deaths across the three arms of the trial in the open phase was subsequently reported by Jelic et al. —there were three deaths in the donepezil group, one in the vitamin E group, and two in the placebo arm; thus, the total number of deaths per arm in the whole trial was ten in the donepezil group [three from cardiac arrest], six in the vitamin E group, and seven in the placebo group.) Although Petersen et al. conceded that the results “do not provide support for a clear recommendation for the use of donepezil in persons with mild cognitive impairment,” they did suggest that their ﬁndings “could prompt a PLoS Medicine | www.plosmedicine.org 0458 April 2006 | Volume 3 | Issue 4 | e140 ...
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This note was uploaded on 10/10/2010 for the course ENG 000121 taught by Professor Mcgrand during the Spring '10 term at Cornell University (Engineering School).
- Spring '10